The present invention relates to a method for treating a patient who is suffering from a dependence on, tolerance of, or addiction to at least one benzodiazepine or is at risk of becoming dependent upon, tolerant of, or addicted to such a drug. More specifically, the invention relates to such a method which comprises administering an amount of melatonin effective to treat or prevent the dependence, tolerance or addiction.
Insomnia is a frequently encountered problem in modern society: it is estimated that almost one third of the U.S. population suffers from this condition to some extent. The problem is particularly troublesome among the elderly. Benzodiazepine hypnotics are among the most commonly used drugs in the therapeutic treatment of insomnia. Although the precise mechanism of action of these drugs on sleep induction has not been completely elucidated, it is assumed that they exert their activity through a benzodiazepine/GABA-A (gamma amino butyric acid) receptor complex. As insomnia is thought to be associated with derangement of the normal sleep-wake cycle, it is possible that the effects of these drugs on sleep induction may be accomplished by phase-shifting the internal biological clock in the brain.
Indiscriminate and/or prolonged use of benzodiazepine hypnotics often results in the development of tolerance to the drugs, and rebound or withdrawal phenomena can appear following abrupt cessation of the drugs. The extent of these phenomena depends upon both the compound and its dosage.
Dependence upon benzodiazepines also often develops in persons seeking to overcome an addiction to a hallucinogenic drug who take one or more benzodiazepines to ease their anxiety and convulsions during withdrawal from the narcotic(s) to which they are addicted.
In the 1990 U.S. National Household Survey of the Use of Psychotherapeutic Medications, about 8% of the medical users of hypnotics advanced a prescribed dose on their own, an increase of 25% over those who responded similarly in a 1979 survey. Inasmuch as the survey found that 2.6% of the U.S. population takes benzodiazepine hypnotics (as compared to 2.4% in 1979), the number of individuals in the U.S. alone who develop tolerance to, and dependence upon, these drugs can be estimated at 560,000. These numbers do not include substance use outside medical or social norms and multiple drug abuse. No method of rapid withdrawal followed by an effective alternative treatment has yet been reported in patients who developed dependence on benzodiazepine hypnotics and this problem is a great obstacle in the rehabilitation and recovery of narcotic drug addicts.
It is well known that melatonin, an indole-derived hormone produced at night by the pineal gland, plays a major physiological role in the regulation of sleep. Melatonin is produced and secreted into the plasma in a circadian rhythm which parallels the sleep-wake cycle. A derangement of the normal, diurnal melatonin production often results in sleep disorders. Melatonin binding sites have been characterized in membrane preparations from mammalian brains. Autoradiographic studies have revealed the existence of melatonin binding sites in the human biological clock.
A reciprocal relationship has been shown to exist between benzodiazepines and melatonin. There is evidence that melatonin affects benzodiazepine receptors. For example, melatonin augments GABA and benzodiazepine binding to brain membranes. In addition, pinealectomy results in a significant decrease, whereas melatonin injections restore, the benzodiazepine receptor density in the cerebral cortex of the rat. See, for example, Cardinali, D. P., et al. Adv. Biochem. Psychopharm. 42:155 (1986); Acun Castroviejo, D., et al. J. Pineal Res. 3:101 (1986); and Niles, L. P., et al. J. Neural Transm. 70:117. Melatonin also can enhance the anxiolytic effects of diazepam in mice (Guardiola-Lemaitre, B., et al. Pharmacol. Biochem. Behav. 41:405 [1992]).
On the other hand, there is evidence that benzodiazepines affect melatonin production. More specifically, benzodiazepines have been reported to suppress the nocturnal rise in plasma melatonin and to shift its day-night rhythmicity in several mammalian species. It has not yet been established whether these effects are indirect through the effect on the circadian clock or due to direct modulation of the pineal gland via benzodiazepine receptors localized on the pinealocytes. It is known that benzodiazepines can potentiate gamma amino butyric acid (GABA)-induced inhibition of melatonin synthesis and secretion (McIntyre, I. M., et al., Biol. Psychiat. 24:105 [1988]) and that nocturnal enhancement of plasma melatonin could be suppressed by benzodiazepines in species. It has not yet been established whether these effects are indirect through the effect on the circadian clock or due to direct modulation of the pineal gland via benzodiazepine receptors localized on the pinealocytes. It is known that benzodiazepines can potentiate gamma amino butyric acid (GABA)-induced inhibition of melatonin synthesis and secretion (McIntyre, I. M., et al., Biol. Psychiat. 24:105 [1988]) and that nocturnal enhancement of plasma melatonin could be suppressed by benzodiazepines in humans, thus leading to distortion in the diurnal melatonin rhythm (Kabuto, M., et al. Endocr. Japon. 33:405[1986]). Moreover, it has been observed that chronic treatment with oxazepam modified the diurnal variations in the density of melatonin receptors at night in the rat brain and that this effect was not observed in pinealectomized animals (Anis, Y., et al. J. Neural Transm. 89:155 [1992]).
It surprisingly has been found that administration of melatonin concurrently with benzodiazepine drugs can (1) wean a patient away from dependence on, tolerance of, or addiction to such drugs and (2) prevent the occurrence of such symptoms in patients who have been diagnosed as requiring a benzodiazepine drug but who have not yet become dependent on, tolerant of, or addicted to that drug.
Thus, one embodiment of the present invention comprises treating a patient suffering from a dependence on, tolerance of, or addiction to at least one benzodiazepine by administering melatonin to the patient on a daily basis in an amount sufficient to treat said dependence, tolerance or addiction.
Another embodiment of the invention comprises treating a patient who has been diagnosed as having a condition susceptible to alleviation by the administration of a benzodiazepine, while simultaneously preventing said patient from becoming dependent on, tolerant of, or addicted to the benzodiazepine, wherein said method comprises administering to the patient said benzodiazepine in an amount effective to alleviate the condition in combination with melatonin in an amount effective to prevent the patient from becoming dependent upon, tolerant of, or addicted to the benzodiazepine.
It has been found that persons who are dependent upon, tolerant of, or addicted to a benzodiazepine typically have developed an endogenous melatonin deficiency or distortion as determined by plasma melatonin level and profile. Accordingly, a further embodiment of the present invention is directed to a method of treating a patient who is suffering from an endogenous melatonin deficiency or distortion due to the prolonged administration of a benzodiazepine drug wherein said method comprises administering to the patient an amount of melatonin which is effective to correct or compensate for the deficiency or distortion. In a preferred embodiment, the melatonin can be administered so as to produce in the patient a plasma melatonin profile which substantially simulates a normal endogenous melatonin profile.
Another embodiment of the invention provides a method for treating a patient who has been clinically diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug and who is risk of developing a melatonin deficiency or distortion, which method comprises administering to the patient a benzodiazepine drug in combination with melatonin on a daily basis wherein the melatonin is administered so as to maintain the patient""s plasma melatonin profile substantially similar to a normal endogenous melatonin plasma profile.
The invention further relates to a pharmaceutical controlled release formulation comprising melatonin in combination with at least one pharmaceutical carrier, diluent or coating, wherein, upon administration to a human, the formulation releases melatonin over time such that the person""s melatonin plasma profile substantially simulates the melatonin plasma profile of a human having a normal endogenous melatonin profile.